Journal Article

Chronic ET<sub>A</sub> receptor blockade prevents endothelial dysfunction of small arteries in apolipoprotein E-deficient mice

Livius V d'Uscio, Matthias Barton, Sidney Shaw and Thomas F Lüscher

in Cardiovascular Research

Published on behalf of European Society of Cardiology

Volume 53, issue 2, pages 487-495
Published in print February 2002 | ISSN: 0008-6363
Published online February 2002 | e-ISSN: 1755-3245 | DOI: http://dx.doi.org/10.1016/S0008-6363(01)00469-2
Chronic ETA receptor blockade prevents endothelial dysfunction of small arteries in apolipoprotein E-deficient mice

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Abstract

Objective: This study investigated whether endothelial dysfunction occurs in mesenteric arteries of apoE-deficient mice and determined the role of endothelin (ET)-1, which is increased in human atherosclerosis, using an orally active endothelin ETA receptor antagonist. Methods: ApoE-deficient and C57BL/6J control mice were fed for 30 weeks with normal chow or high-fat Western-type diet alone or in combination with darusentan (LU135252; 50 mg/kg/day). Vasomotor reactivity of isolated small mesenteric arteries (I.D. 200–250 μm) was studied in vitro under perfused and pressurized conditions. Results: In both mouse strains, about one fourth of the endothelium-dependent relaxant response to acetylcholine was insensitive to inhibition by l-NAME and indomethacin. In mesenteric arteries of apoE-deficient mice on Western-type diet, increased intima-media thickness and levels of endothelin-1 protein were observed. In addition, NO-mediated endothelium-dependent relaxation to acetylcholine was reduced without affecting l-NAME/indomethacin insensitive relaxation and contractions to endothelin-1 and serotonin were enhanced. Treatment with darusentan normalized vascular structure, NO-mediated relaxation to acetylcholine and contractions to endothelin-1 and serotonin without affecting blood pressure or plasma cholesterol levels. Conclusions: Severe hypercholesterolemia in apoE-deficient mice is associated with attenuation of NO-mediated relaxation to acetylcholine and increased vascular endothelin-1 content. Chronic ETA receptor blockade may provide a new therapeutic approach to improve NO-mediated endothelium-dependent vasomotion in small arteries.

Keywords: Endothelins; Endothelial receptors; Endothelial function; Lipoproteins; Nitric oxide

Journal Article.  4901 words.  Illustrated.

Subjects: Cardiovascular Medicine

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